Inhibition of TrkB at the nucleus accumbens, using ANA-12, regulates basal and stress-induced orexin A expression within the mesolimbic system and affects anxiety, sociability and motivation.

Repeated stress exposure can lead to the development of anxiety and mood disorders. An emerging biological substrate of depression and associated pathology is the nucleus accumbens (NAc), which through interactions with limbic, cognitive and motor circuits can regulate a variety of stress responses. Within these circuits, orexin neurons are involved in arousal and stress adaptability, effects proposed mediated via brain-derived neurotrophic factor signaling. This study tested the hypotheses that 1) repeated exposure to heterotypic stress alters social ability and preference and passive avoidant behaviors, 2) TrkB receptors at the NAc shell regulates stress-induced behavioral responses and orexin expression within the mesocorticolimbic system. Our findings indicate that ANA-12 (0.25 μg/0.5 μl) enhanced sociability during the social interaction test, although treatment had no effect on social preference. The development of conditioned place preference, and fear retention in the passive avoidance test were also facilitated by ANA-12. Biochemical assessments on brain tissues collected within 2 h of a forced swim exposure revealed that ANA-12 increased orexin A immunoreactivity (ir) in the hypothalamic perifornical area, while expression was reduced in the ventral portion of the hippocampal CA1 layer, irrespective of the stress condition. This contrasts changes at the VTA characterized by elevated versus reduced orexin A-ir in ANA-12-treated stress and non-stress rats, respectively. Colocalized orexin A- and tyrosine hydroxylase (TH)-ir at the VTA supports a different temporal expression post stress, TH-ir being unaffected 9 days post stress. These findings support a role for TrkB receptors in regulating basal and stress-induced social, cognitive and motivational behavior, and modulatory actions of BDNF, via TrkB signaling, on orexin A signaling upon stress exposure.